title: Heme impairs the ball-and-chain inactivation of potassium channels.
abstract: Fine-tuned regulation of K(+) channel inactivation enables excitable cells to adjust action potential firing. Fast inactivation present in some K(+) channels is mediated by the distal N-terminal structure (ball) occluding the ion permeation pathway. Here we show that Kv1.4 K(+) channels are potently regulated by intracellular free heme; heme binds to the N-terminal inactivation domain and thereby impairs the inactivation process, thus enhancing the K(+) current with an apparent EC50 value of ∼20 nM. Functional studies on channel mutants and structural investigations on recombinant inactivation ball domain peptides encompassing the first 61 residues of Kv1.4 revealed a heme-responsive binding motif involving Cys13:His16 and a secondary histidine at position 35. Heme binding to the N-terminal inactivation domain induces a conformational constraint that prevents it from reaching its receptor site at the vestibule of the channel pore.
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany.
authors.forename: Nirakar
authors.initials: N
authors.lastname: Sahoo
authors.forename: Nishit
authors.initials: N
authors.lastname: Goradia
authors.forename: Oliver
authors.initials: O
authors.lastname: Ohlenschläger
authors.forename: Roland
authors.initials: R
authors.lastname: Schönherr
authors.forename: Manfred
authors.initials: M
authors.lastname: Friedrich
authors.forename: Winfried
authors.initials: W
authors.lastname: Plass
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006418:Heme / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017136:Ion Transport / Q000502:physiology; D051665:Kv1.4 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D014982:Xenopus laevis
chemical_list: D051665:Kv1.4 Potassium Channel; D006418:Heme
keywords: A-type channel; N-type inactivation; NMR; cysteine; intrinsically disordered domain